Farnesyl transferase inhibitors

Abstract

A family of tetrahydroimidazo[1,2a]pyrazine based compounds capable of inhibiting the activity of farnesyl transferase and treating tumors and restenosis having the following structure: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the specification.

1. A compound having the formula (I):                  
 
       wherein:
 R 1  is H, lower alkyl, cycloalkylthio, or lower alkylthio, or, together with R 2 , form —CH 2 — or —C(CH 3 ) 2 —; 
 each of R 2  and R 3 , independently, is H or lower alkyl; 
 R 4  is H 2  or O; 
 R 5  is H, or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is lower alkyl, —O—R 10 , —S(O) m R 10  (where m is 0, 1, or 2), —N(R 10 )(R 11 ), —N—C(O)—R 10 , —NH—(S 2 )—R 10 ; —CO 2 —R 10 , —C(O)—N(R 10 )(R 11 ), or —(SO 2 )—N(R 10 )(R 11 ); 
 each of R 6  and R 7 , independently, is H, —C(O)NHCHR 13 CO 2 R 14 , or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, aryloxy, aryl lower alkoxy, —N(R 10 )(R 11 ), —COOH, —C(O)—N(R 10 )(R 11 ), or halo; 
 each of R 8  and R 9 , independently, is H, or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, —N(R 10 )(R 11 ), —COOH, —C(O)—N(R 10 )(R 11 ), or halo; and 
 each of R 10  and R 11 , independently, is H, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl; 
 R 12  is NR 9 , S, or O; 
 R 13  is substituted or unsubstituted lower alkyl wherein the substituent is lower alkyl, —OR 10 ,S(O) m R 10  (wherein m is 0, 1, or 2) or —N(R 10 )(R 11 ); and 
 R 14  is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A compound of  claim 1 , wherein each of R 8  and R 9 , independently, is H; or a pharmaceutically acceptable salt thereof. 
     
     
       3. A compound of  claim 2 , wherein R 7  is H; or a pharmaceutically acceptable salt thereof. 
     
     
       4. A compound of  claim 3 , wherein R 6  is substituted or unsubstituted aryl or cylcoalkyl, and R 5  is substituted or unsubstituted lower alkyl, cycloalkyl, or cycloalkyl lower alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
       5. A compound of  claim 4 , wherein each of R 1 , R 2 , and R 3 , independently, is H; or a pharmaceutically acceptable salt thereof. 
     
     
       6. A compound of  claim 2 , wherein R 6  is H; or a pharmaceutically acceptable salt thereof. 
     
     
       7. A compound of  claim 6 , wherein R 7  is substituted or unsubstituted aryl or cycloalkyl, and R 5  is substituted or unsubstituted lower alkyl, cycloalkyl, or cycloalkyl lower alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
       8. A compound of  claim 7 , wherein each of R 1 , R 2 , and R 3 , independently, is H; or a pharmaceutically acceptable salt thereof. 
     
     
       9. A compound of  claim 2 , wherein R 5  is substituted or unsubstituted lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, R 6  is halo or substituted or unsubstituted cycloalkyl or aryl, and R 7  is halo or substituted or unsubstituted cycloalkyl or aryl. 
     
     
       10. A compound of  claim 9 , wherein each of R 1 , R 2 , and R 3 , independently, is H; or a pharmaceutically acceptable salt thereof. 
     
     
       11. A compound of  claim 1 , wherein said compound is of the formula:
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(3-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-(2-hydroxy-methyl)-2-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-3-thio-propyl)-8-butyl-3-phenyl-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-2-(2-methoxyphenyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thio-propyl)-8-butyl-2-(2-hydroxyphenyl)-5,6,7,8-tetrahydro-imidazo-[1,2a]-pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(2-methylpropyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2(2-hydroxy-6-methoxyphenyl)-5,6,7,8-tetrahydro[1,2a]pyrazine; 
 2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-7-((thiazolidin-4-yl)carbonyl)-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo-[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(4-methoxycyclohexyl)methyl-2-(2-methoxyphenyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine(cis isomer); 
 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(4-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(3-piperidinylmethyl)-5,6,7,8-terahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(1-naphthyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(2-methylthio)-ethyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(3-indolinylmethyl)-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; and 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylimidazol-3-yl)methyl-2-(2-methoxyphenyl)-8-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; or in the form of enantiomers or enantiomeric mixtures; or pharmaceutically acceptable salts thereof. 
 
     
     
       12. A compound consisting of a first compound and a second compound wherein each of said first compound and each of said second compound is independently selected from the group consisting of a compound of formula (I):                  
 
       wherein:
 R 1  is H, lower alkyl, cycloalkylthio, or lower alkylthio, or, together with R 2 , form —CH 2 — or —C(CH 3 ) 2 —; 
 each of R 2  and R 3 , independently, is H or lower alkyl; 
 R 4  is H 2  or O; 
 R 5  is H, or substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is lower alkyl, —O—R 10 , —S(O) m R 10  (where m is 0, 1, or 2), —N(R 10 )(R 11 ), —N—C(O)—R 10 , —NH—(SO 2 )—R 10 , —CO 2 —R 10 , —C(O)—N(R 10 )(R 11 ), or —(SO 2 )—N(R 10 )(R 11 ); 
 each of R 6  and R 7 , independently, is H, —C(O)NHCHR 13 CO 2 R 14 , or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, aryloxy, aryl lower alkoxy, —N(R 10 )(R 11 ), —COOH, —C(O)—N(R 10 )(R 11 ), or halo; 
 each of R 8  and R 9 , independently, is H, or substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkyl lower alkyl, cyloalkenyl, cycloalkenyl lower alkyl, aryl, aryl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl, wherein the substituent is OH, lower alkyl, lower alkoxy, —N(R 10 )(R 11 ), —COOH, —C(O)—N(R 10 )(R 11 ), or halo; and 
 each of R 10  and R 11 , independently, is H, lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, heterocyclyl, or heterocyclyl lower alkyl; 
 R 12  is NR 9 , S, or O; 
 R 13  is substituted or unsubstituted lower alkyl wherein the substituent is lower alkyl, —OR 10 , S(O) m R 10  (wherein m is 0, 1, or 2) or —N(R 10 )(R 11 ); and 
 R 14  is H or lower alkyl; 
 wherein R 1  in said first compound and R 1  in said second compound in combination, form a disulfide bond; or a pharmaceutically acceptable salt thereof. 
 
     
     
       13. A compound of  claim 12 , wherein said first and second compounds are identical; or a pharmaceutically acceptable salt thereof. 
     
     
       14. A compound of  claim 13 , wherein said compound is of the formula:
 bis-1,1′-[2-amino-3-(7-butyl-2-(2-methoxyphenyl)-4,5,6,7-tetrahydro-imidazo[1,2a]piperazine-6-yl)-3-oxo]propyl disulfide; 
 bis-1,1′-[2-amino-3-(2-(2-methoxyphenyl)-7-(2-methylpropyl)-4,5,6,7-tetrahydro-imidazo[1,2a]piperazine-6-yl)-3-oxo]propyl disulfide; 
 bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl)disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1,2a]-pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[2-amino-3-(8-butyl-2-cyclohexyl-5,6,7,8-tetrahydro-imidazo-[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide; 
 bis-1,1′-[2-amino-3-(3-bromo-8-butyl-2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2a]-pyrazin-7-yl)-3-oxo-propyl]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[2-amino-3-(2-cyclohexyl-8-(cyclohexylmethyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazin-7-yl)-3-oxo-propyl]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; or 
 bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxycyclohexyl)-methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulfide; or in the form of enantiomers or enantiomeric mixtures or pharmaceutically acceptable salts thereof. 
 
     
     
       15. A method of treating a ras-dependent tumor or restenosis caused by benign cell proliferation in a subject, which comprises administering to said subject a therapeutically effective amount of the compound or salt of  claim 1 . 
     
     
       16. A method of treating a ras-dependent tumor or restenosis caused by benign cell proliferation in a subject, which comprises administering to said subject a therapeutically effective amount of the compound or salt of  claim 12 . 
     
     
       17. A method of treating a ras-dependent tumor according to  claim 15  wherein said tumor is located in or on the breast, the prostrate gland, the colon, a lung, an ovary, the epidermis or the pancreas of a mammal. 
     
     
       18. A method of treating a ras-dependent tumor according to  claim 16  wherein said tumor is located in or on the breast, the prostrate gland, the colon, a lung, an ovary, the epidermis or the pancreas of a mammal. 
     
     
       19. A method of treating a ras-dependent tumor according to  claim 15  wherein said tumor is a hematopoietic tumor found in a mammal. 
     
     
       20. A method of treating a ras-dependent tumor according to  claim 16  wherein said tumor is a hematopoietic tumor found in a mammal.